Prognostic role of simple inflammatory biomarkers in patients with severe COVID-19: an observational study.

BACKGROUND/AIM: Simple inflammatory biomarkers, such as neutrophil to lymphocyte ratio (NLR), could serve as prognosis indicators in patients with Coronavirus disease 2019 (COVID-19). The utility of on-admission inflammatory biomarkers in predicting outcomes was investigated in patients suffering from severe COVID-19 infection. METHODS: We performed a retrospective study to assess the role of white blood count (WBC), neutrophils (N), lymphocyte (L), platelets (PLTs), C-reactive protein (CRP), reverse transcription polymerase chain reaction (RT-PCR), NLR (N/L), PLR (P/L), dv (derived variation of)-NLR (N/WBC-L), LNR (L/N), dv (derived variation of)-LNR (L/WBC-N), and CLR (CRP/L), in predicting the need for high-flow nasal cannula (HFNC) use, admission to Intensive Care Unit (ICU), and death in adult patients with severe COVID-19 admitted to the Department of Respiratory Medicine from April to September 2021. RESULTS: One hundred and fifteen patients (60 % males) with a mean age of 57.7 ± 16.3 years were included. Thirty-seven patients (32.2 %) required escalation with HFNC, eight patients (7 %) were admitted to the ICU, and nine patients (7.8%) died. Based on univariate analysis, CRP [odds ratio (OR): 1.25, 95 % confidence interval (CI): 1.1-1.42), LNR (OR: 0.015, 95 % CI: 0.00-0.35), dv-NLR (OR: 5*106, 95 % CI: 26.7-9*109), CLR (OR: 7*1058, 95 % CI: 3*1025-2*1092), length of hospitalization (LOH; OR: 1.44, 95 % CI: 1.22-1.63), dyspnea at presentation (OR: 2.83, 95 % CI: 1.23-6.52), and ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) on admission (OR: 0.967, 95 % CI: 0.952-0.983) were independent predictors for oxygen requirements. However, the multivariate analysis showed that LNR (OR: 1.686e0-4, 95 % CI: 6.441e00-8-0.441), PaO2/FiO2 on admission (OR: 0.965, 95 % CI: 0.941-0.989), and LOH (OR: 1.717, 95 % CI: 1.274-2.314) were the most important predictor for HFNC use. Nasal congestion at presentation (OR: 11.5, 95 % CI: 1.61-82.8) was a unique and independent predictor for ICU admission. As far as death is concerned, the univariate analysis identified elevated CRP (OR: 1.11, 95 % CI: 1.0-1.24), low RT-PCR (OR: 0.829, 95 % CI: 0.688-0.999), high CLR (OR: 3.2*1033, 95 % CI: 5.8-1.8*1066), age (OR: 1.08, 95 % CI: 1.02-1.14), body mass index (BMI) over 30 (OR: 5.25, 95 % CI: 1.26-21.96), the chronic use of angiotensin-converting enzyme inhibitors (OR: 5.72, 95 % CI: 1.35-24.09), nitrates (OR: 14.85, 95 % CI: 1.81-121.8), diuretics (OR: 8.21, 95 % CI: 1.97-34.32), PaO2/FiO2 on admission (OR: 0.983, 95 % CI: 0.970-0.998), and nasal congestion at presentation (OR: 9.81, 95 % CI: 1.40-68.68) as independent predictors. However, the multivariate analysis pinpointed that obesity (BMI >30) (OR: 10.498, 95 % CI: 1.107-99.572) remained the most important predictor for death. CONCLUSION: LNR and PaO2/FiO2 on admission could be used to timely identify patients requiring HFNC during hospitalization, while obesity (BMI >30) could be an independent predictor of death. Nasal congestion emerges as a unique predictor for ICU admission. HIPPOKRATIA 2022, 26 (2):70-77.

Low molecular weight heparins use in pregnancy: a practice survey from Greece and a review of the literature.

BACKGROUND: Use of LMWH in pregnancy is not only limited to VTE management, but it extends, to the management of vascular gestational complications and the optimization of IVF pregnancies despite the lack of concrete scientific evidence. In this context, we conducted the present study aiming to gain insights regarding the use of LMWH during pregnancy and puerperium. We recorded indication for use, diagnostic work-up as well as the safety and efficacy of the treatment, trying to elucidate the clinical practice in our country. METHODS: We analyzed data regarding 818 pregnant women received LMWH during 2010-2015.Our cohort had a median age of 33.9 years and a BMI of 23.6.There were 4 groups: those with a history of VTE [Group-A: 76], those with pregnancy complications [Group-B: 445], those undergoing IVF [Group-C: 132] and those carrying prothrombotic tendency (thrombophilia, family history of VTE, other) [Group-D: 165]. Mean duration of LMWH administration was 8.6 ± 1.5 months. Out of the total number, 440 received LMWH in fixed prophylactic dose, 272 in higher prophylactic-weight adjusted dose and 106 in therapeutic dose. Moreover, 152 women received in addition low-dose acetylsalicylic acid (ASA). 93.8% of pregnancies were single and 6.2% were multiple ones. Live births occurred in 98.7% of pregnancies. RESULTS: Anticoagulation was efficacious and well tolerated. Seventeen VTE events were recorded; 7 of them antepartum and 10 postpartum. No major bleeding events were observed while 13 clinical relevant non-major bleeding events were recorded. Regarding gestational vascular complications, 28 IUGR events were recorded, as well as 48 cases of preterm labor of which 12 were concomitant with IUGR (25%). Six early pregnancy losses were recorded; there were 3 fetal deaths and 3 cases of pre-eclampsia/eclampsia. CONCLUSIONS: LMWHs are used extensively during pregnancy and puerperium in Greece for VTE treatment and prophylaxis and for a variety of other indications as well. Although the drug has been shown to be both safe and efficacious, its use for some indications has no proven scientific evidence. In order to clearly define the role of LMWHs in pregnancy, beyond thromboprophylaxis, large prospective studies are required, which could be based on the conclusions of this study.

Increased microvascular network in bone marrow of HIV-positive haemophilic patients.

OBJECTIVES: Angiogenesis has been associated with the pathogenesis of myelodysplastic syndromes (MDSs). However, less is known about the significance of this process in the bone marrow of HIV-positive patients with myelodysplastic features (MDF). METHODS: Trephines from 22 HIV-positive haemophilic patients were immunostained for CD34 antigen, and the microvessel density (MVD) was quantitatively evaluated and compared with that of 21 biopsies from patients with primary MDS and with that of 12 control bone marrows with no evidence of marrow disease. RESULTS: Bone marrow MVD in HIV-positive haemophilic patients was similar to that in patients with MDS; however, both groups revealed significantly higher MVD counts than those of control bone marrows (P=0.002). Mean MVD counts of HIV-positive haemophilic patients were significantly associated with HIV RNA levels (P=0.008). In contrast, no correlation was found between MVD and clinical HIV stage or CD4 counts at the time of biopsy. CONCLUSIONS: These results suggest a direct involvement of HIV in the pathogenesis of MDF in HIV infection. Elucidation of the mechanisms underlying bone marrow angiogenesis in HIV-positive patients may provide further insights into the pathobiology of AIDS.

13q deletion in chronic lymphocytic leukemia: characterization of E4.5, a novel chromosome condensation regulator-like guanine nucleotide exchange factor.

We report the characterization of a new gene (E4.5) that maps at chromosome band 13q14.3, a chromosomal area frequently deleted in chronic lymphocytic leukemia (CLL) and in other lymphoid malignancies. E4.5 gene encodes for a 4 kb mRNA expressed in various tissues and has an open reading frame of 531 amino acids. The predicted E4.5 protein shows strong homology with the human regulator of chromosome condensation (RCC1) protein, the principal GTP exchange factor for Ran protein. The E4.5 protein contains a BTB domain in its N-terminus, a protein-protein interaction motif. Therefore, we propose that E4.5 is a new member of the RCC1-related guanine nucleotide exchange factor (GEF) family with potent interaction with other proteins and unknown function. Until now, no tumor suppressor genes have been mapped in the 13q14.3 minimal deleted region (MDR) in patients with CLL. It has been proposed that loss of the 13q14.3 MDR may contribute to lymphoid neoplasia by altering the expression/function of genes located on 13q14.3 outside the MDR. The E4.5 is one of these genes with a potential role in the pathogenesis of CLL.

Deletion analysis of chromosome 13q14.3 and characterisation of an alternative splice form of LEU1 in B cell chronic lymphocytic leukemia.

Heterozygous and homozygous deletions of chromosome 13q14.3 are found in 50% of patients with B cell CLL, suggesting the presence of one or more tumour suppressor genes within the deleted region. To identify candidate genes from the region, we constructed a map of 13q14.3 using a combination of genomic and cDNA library screening. The incidence of deletions in CLL patients was 51.5% encompassing a 265 kb region of minimal deletion (RMD) telomeric to markers D13S319. Two CpG islands were identified within the RMD, the telomeric of which is fully methylated whilst the more centromeric is unmethylated. A novel transcript was identified within the RMD that represents an alternative splice version of Leu1. The nine exons of this transcript span a genomic of 436 kb with exon 1 of Leu1 being the common first exon. The remaining exons were shown to be more frequently deleted than Leu1 itself. All splice forms of this transcript were detectable by RT-PCR but Leu1 detected the most abundant message on Northern blotting. Sequence analysis failed to reveal inactivating mutations in patients with heterozygous deletion of 13q14.3, although a polymorphic T to A variant was identified within exon 1 of Leu1 in leukemic and normal controls. As no mutations have been detected for Leu1 or any other transcript so far described, we cannot exclude the existence of control elements within the RMD that may regulate expression of genes lying in this region.

Mzf1 controls cell proliferation and tumorigenesis.

MZF1 is a transcription factor belonging to the Krüppel family of zinc finger proteins, expressed in totipotent hemopoietic cells as well as in myeloid progenitors. Here we have inactivated Mzfi1 by gene targeting. Mzf1(-/-) mice develop lethal neoplasias characterized by the infiltration and complete disruption of the liver architecture by a monomorphic population of cells of myeloid origin reminiscent of human chloromas. Mzf1 inactivation results in a striking increase of the autonomous cell proliferation and of the ability of Mzf1(-/-) hemopoietic progenitors to sustain long-term hemopoiesis. These findings demonstrate that Mzf1 can act as a tumor/growth suppressor in the hemopoietic compartment.

Impaired Fas response and autoimmunity in Pten+/- mice.

Inactivating mutations in the PTEN tumor suppressor gene, encoding a phosphatase, occur in three related human autosomal dominant disorders characterized by tumor susceptibility. Here it is shown that Pten heterozygous (Pten+/-) mutants develop a lethal polyclonal autoimmune disorder with features reminiscent of those observed in Fas-deficient mutants. Fas-mediated apoptosis was impaired in Pten+/- mice, and T lymphocytes from these mice show reduced activation-induced cell death and increased proliferation upon activation. Phosphatidylinositol (PI) 3-kinase inhibitors restored Fas responsiveness in Pten+/- cells. These results indicate that Pten is an essential mediator of the Fas response and a repressor of autoimmunity and thus implicate the PI 3-kinase/Akt pathway in Fas-mediated apoptosis.

Genetics of small lymphocyte disorders.

Cytogenetic analysis of small lymphocytes disorders is hindered by the low mitotic activity of the malignant cells. The use of fluorescence in situ hybridization (FISH) allows the detection of chromosomal amplifications, deletions, or translocations at a single-cell level in dividing and resting cells. The use of FISH in combination with other molecular techniques has defined the deletion in band 13q14 as the most common abnormality in chronic lymphocytic leukemia, followed by del (11)(q22-23), trisomy 12, del (17)(p13), and del (6)(q21). The del 13q14 is also found in 70% of mantle-cell lymphomas (MCLs) and in non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) patients. These findings point to the existence of yet unidentified tumor-suppressor gene(s) at the 13q14 locus, the loss/inactivation of which leads to B-cell neoplasia. Del (17(p13) (involving the p53 tumor-suppressor gene) and del (11)(q22-23) (involving the ataxia-telangiectasia gene [ATM]) seem to be independent prognostic factors for poor survival in chronic lymphocytic leukemia (CLL) patients. In MCL, the t(11;14) involving the bcl-1 gene is found, but data from a bcl-1 transgenic animal model suggest that hyperexpression of bcl-1 is not sufficient for lymphomatogenesis. Similar data are observed in bcl-2 transgenic animals, a finding showing that the bcl-2 hyperexpression observed in t(14;18)-positive follicular lymphoma cells is not sufficient to confer a malignant phenotype. The contribution of other chromosomal abnormalities other than bcl-1 and bcl-2 rearrangements in the pathogenesis of MCL and follicular-cell lymphomas has to be determined.